Rapid preparation of encapsulation formula



Unite RAPID PREPARATION OF ENCAPSULATION FORMULA No Drawing. Application September 25, 1953, Serial No. 382,472

11 Claims. (Cl. 106-135) This invention relates to improvements in a method for preparing a gelatin composition to be cast in a strip from which soft gelatin capsules are manufactured.

Conventional methods of preparing the gelatin composition include chilling all components, mixing them and permitting the gelatin to be slowly hydrated. The mixture is then melted preferably under a vacuum and held under a vacuum until free from air bubbles and then used. Procedures of this nature are slow and time consuming. Holding the gelatin composition under the molten conditions until air bubbles are released entails not only the delay and the use of extra equipment, but also causes the gelatin to be degraded by hydrolysis during the time of storage.

It has now been found that the problem of hydration.

of the gelatin is largely the problem of extremely rapid mixing and that not only can the materials be mixed rapidly, but that elevated temperatures can be used with superior results providing that the correct conditions are used.

A vacuum tight mixer of the sigma arm or bladed type is used in which preferably the entire volume is swept by agitator blades. Preferably the mixer is one in which the agitator drive is in the upper portion of the mixer so that any leakage of air around the drive shaft is released above the level of the gelatin composition. The mixer should have temperature control means. A jacketed mixer in which steam or hot water is supplied to the jacket is preferred, although electrical elements, or other form of heating may be used.

The mixer should be air tight and easily opened. To the mixer is added the gelatin, usually in flake or granular form, and any pigments, dyes, preservatives and flavors which are solid, but soluble, may be added to the dry gelatin, or may be dissolved in the liquids.

Adding all of the solids to the dry gelatin is preferred, as it saves the time and stirring necessary to ensue solution of solids in the liquids, saves alcohol which may be necessary for difficulty soluble solids, and enables all of the dry components to be used together. Residual web may be added with the dry components. T he mixer is closed and a vacuum applied to the solids as they are stirred.

The vacuum is preferably applied slowly, with agitation of the solids, so that trapped air does not cause undue blowing or dusting. The mixer may be hot from a preceding run or may be heated during the agitation. The agitation of the solids under vacuum causes the withdrawal of any trapped and absorbed air. The heat assistsin the release of the air and partially warms the solids so that the mixing cycle is shortened. The jacket may be steam heated, but the gelatin itself should not be heated above about 85 C. v

To save time, during the evacuation of the mixer, and the mixing and de-aeration of the solids, the liquids, which include water and glycerin, are mixed and heated. Alcohol, dyes, preservatives and flavors which are not incorporated with the dry solids are added to and dissolved tateS at n l 2 ,799,591 Patented July 16, 1957 in the liquids. The liquids are preferably heated to between about '50 C. and 100 C. This assists in the release of any dissolved air and permits very rapid heat transfer to the liquid in a stirred kettle.

, Heat may more rapidly be added to the liquids before mixing with the solids, as the aqueous fluid has a much higher heat transfer coefiicient than the gelatin composition. If alcohol or other volatile material is present, the liquids should be kept at a lower temperature than boiling to avoid losses. A temperature of 82 to 88 C. is particularly convenient.

Agitation in the mixer is preferably stopped and the heated liquids are drawn into the mixer by vacuum. Preferably the vacuum source is closed ofi from the mixer while the liquids are being drawn in, to avoid losses from splashing. Any dissolved air remaining in the liquids flash, and are removed as the hot liquids are fed into the evacuated mixer. The feed lines should be large enough so that the entire charge of liquid is drawn into the mixer in a short time, less than 1 minute being preferred. If available equipment renders it desirable, the water and glycerin may beheated and drawn into the mixer separately. Vacuum is re-applied to the mixer if the pressure has risen, and the agitators promptly started. Less balling and clogging in the mixer occur if the agitators are stopped during the addition of the hot liquid, although they may be allowed to run continuously. By starting the agitators immediately after the addition of the liquid, the solids and the liquids are intimately mixed before any appreciable hydration of the gelatin has occurred and a thin slurry is formed of the gelatin suspended in the liquid.

The temperature and heat content of the mixer itself, the dry solids and the hot liquids should be adjusted so that the temperature of the final mixture is between about C. and 85 C. Between about and 70 C. is preferred. The liquids may be cooler if the mixer and solids are hotter, and vice versa.

Heat istapplied as necessary to bring the mixture up to the desiredtemperature, but if the heat capacity of the mixer and the temperature of the hot liquids are properly chosen, the mixture is at approximately the desired temperature as soon as blending has occurred. The gelatin rapidly and uniformly becomes hydrated by the water. A uniform smooth mixture is formed. As the whole operation is conducted under vacuum, there is no opportunity for air to be trapped in the mixture and an air free gelatin mix results. As the gelatin dissolves or hydrates, the composition is hot enough to remain thin, and agitation and handling is reasonably convenient.

If the temperature of the initial mixture is below about 45 C., themixtu're as it hydrates becomes very viscous, and may stall or damage the agitator in the mixer. If the temperature is hotter, the gelatin dissolves to a thinner liquid, and no thick stage occurs.

Agitation may be stopped, the vacuum in the mixer released, and up to of a recovered web from the capsulating machines, that is the strip remaining after the capsules have been formed and cut out, may be added to the mixer. If recovered Web is added; a slight excess" of water in the initial composition is used'asthe web has a slightly low water content. The mixer is then sealed and evacuated and after full vacuum is obtained, the agitators are started again, and the mixture stirred until homogeneous and heated as necessary to obtain the deat room temperature, the desired casting temperature is morerapidly obtained:

By using hot liquids and a hot mixer, a batch of 1,000 kilos of gelatin composition for casting can be prepared in a commercial s'iz'e' installation in about 2 hours.

The composition may be conveniently transferred by air pressure from the mixer through a discharge pipe to a holding tank which feeds the casting machines.

By applying the vacuum to the powder to remove air therefrom and permitting the air in the hot liquid to flash as it is drawn into the. hot mixer, an air free composition may be rapidly and conveniently obtained.

It is to be understood that the water soluble ingreclients may be either mixed with the dry gelatin or dissolved in the liquids and that the relative proportions'of gelatin, glycerin and water andthe minor components such as dyes, pigments, preservatives and flavors may be varied over a considerable range to produce the desired composition at the end of the mixing cycle.

The final temperature of the composition during mixing may be between about 43 and 85 C., with between about 63 and 74 C. being particularly convenient. The somewhat higher temperature is convenient during the mixing operation, as a thinner composition which ismore easily handled results. If the gelatin composition remains at a high temperature too long, the gelatin loses its strength. The composition is conveniently prepared at temperature up to about 85 C., and cooled to between about 43 C. and 49 C. while being transferred to the holding tanks, and stored therein for use in feeding the casting machines.

As illustrative of our invention, the following examples are presented.

' Example 1 In an agitator-equipped jacketed, vacuum tight mixer were blended 230 kilograms of 200 Bloom strength gelatin, 504 grams of beta naphthol, 384 grams of methyl para-aminobenzoate, 96 grams of propyl para-aminobenzoate, 576 grams of ethyl vanillin, 1600 grams of red pigment, 1600 grams of titanium dioxide, and 1600 grams of red dye. The mixer was covered and a full vacuum of approximately 28 inches was slowly applied, with the agitators running. Hot water was cycled through the mixer at approximately 78 C.

p In a separate steam jacketed kettle, a mixture of 167.52 kilograms of distilled water, 86.4 kilograms of glycerin, and 7.2 liters of 95% ethyl alcohol were mixed and heated to a temperature of 85 C. After the mixer had blended the powders under vacuum for /2 hour, the agitators were turned off and the vacuum valve closed. The hot solution of water, glycerin and alcohol was drawn into the mixer by vacuum in the mixer, the operation requiring approximately 30 seconds. in the mixer was approximately 24 inches; approximately equal to the vapor pressure of water at the mixture temperature. The agitators were immediately turned on so that the gelatin and the water were intimately mixed before any of the gelatin became appreciably hydrated. A thin slurry developed which thickened as the gelatin became hydrated. The water in the jacket of the mixer was maintained at 67 C. The temperature of the gelatin composition was approximately 67 C. and was ready for casting after 1% hours agitation.

Example 2 The mixer used in the preceding example was loaded with one-half the quantities of dry components set forth in the preceding Example 1, and thereto was added 160 kilograms of residual web from a preceding encapsulating run. The moisture content of the web was 33.5% when added. The full vacuum was drawn and the agitators turned on for a period of one-half hour. During this period, in a steam jacketed kettle, were mixed 101.26

The vacuum 4 kilograms of distilled water, 43.2 kilograms of glycerin and 3.6 liters of ethyl'alcohol. The liquid mixture was heated to 85 C. After the water, glycerin and alcohol reached a temperature of 85 C. and the mixer had agitated the dry materials for one-half hour, the agitators were turned off, the vacuum line closed and the liquids drawn into the mixer by the vacuum. About ten minutes before the end of the dry mixing time, water, at 67 C. was introduced into the jacket. The time for liquid transfer approximately 30 seconds. The agitators were turned on and the vacuum reconnected. The jacket was maintained at 67 C. and after approximately'2 hours, total elapsed time, the gelatin was melted, blended and ready to be transferred to the holding tanks for the casting machines.

Example 3 The procedure of Example 2 was followed, except that the residual web was not added to the dry gelatin, but was held separate for one-half hour after the liquids had been drawn into the mixer. The agitators were stopped, the vacuum released, the mixer opened, and the web was dropped into the mixer. The mixer was closed andvacuum reapplied. After a vacuum equal approximately to that of water vapor at the temperature was reached; the agitators were again started and mixing continued for approximately 45 minutes. The mixture was then homogeneous, uniform and then ready to be fed to the casting machines.

Example 4 In an agitator-equipped, jacketed, vacuum type mixer was placed 230 kilograms of dry 200 Bloom strength gelatin, the mixer covered and a vacuum of approximately and a mixture of 167.52 kilograms of distilled water, and

86.4 kilograms of glycerin at approximately C. were added without breaking the vacuum. As soon as the hot liquids were added, which took approximately 30 seconds, the agitators were again started, giving a thin slurry of solid gelatin suspended in the liquids, which rapidly melted to a uniform gelatin mixture. The temperature of the mixture of gelatin andthe liquids was approximately 70 C. as formed. The steam was turne'd'off and stirring continued for an additional 30 minutes to insure uniformity. The mixture was pumped by air pressure through a jacketed line to a holding tank, cooling water being used in the holding tank andjacket so that the temperature of the mixture dropped to 49 C. in a short period. The colorless gelatin composition serves as an excellent encapsulating material, and because it is colorless, it has the advantage that the contents may be colored and the same transparent shell composition used with different colored capsule contents.

Example 5 In an agitator-equipped, jacketed, vacuum tight mixer were blended 230 kilograms of dry gelatin, 504 grams of beta naphthol, 384 grams of methyl para-aminobenzoate, 96 grams of propyl para-aminobenzoate, 576 grams of ethyl vanillin, 1600 grams of red pigment, l600' grams of titanium dioxide, and 1600' grams of red dye. The mixer was covered and a full vacuum of approximately 28 inches was slowly applied, with the agitators running. Hot water was circulated through the mixer jacket at approximately 78 C. V

In a separate steam jacketed kettle, a mixture of 167.52 kilograms of distilled water, and 86.4 kilograms of glycerin were mixed and heated to a temperature of 85 C. After the mixer had blended the dry solids under vacuum for one-half hour, the agitators were turned off and the vacuum valve closed. The hot solution of water and glycerin were drawn into the mixer by the vacuum in the mixer, the operation requiring approximately 30 seconds. The vacuum in the mixer was approximately 24 inches; approximately equal to the vapor pressure of water at the mixture temperature. The agitators were immediately turned on so that the gelatin and the water were intimately mixed before any of the gelatin became appreciably hydrated. A thin slurry resulted which thickened as the gelatin became hydrated and dissolved. The water in the jacket of the mixer was maintained at 67 C. after the addition of the liquids. The composition was ready for casting after 1 /2 hours agitation.

Example 6 Example 4 was repeated, except that the water and the glycerin were individually heated and drawn into the mixer, the water first and then the glycerin the additions being made rapidly, and as soon as the additions were made the mixture was stirred. The product appeared identical with that obtained in Example 4.

Example 7 Example 6 was repeated, except that the hot glycerin was added first and then the hot water. The product appeared identical with that of Examples 4 and 6.

The vacuum used during the blending may vary from 10 to 28 inches of mercury or more. It is preferred to use a vacuum which is almost sufiicient to cause water to boil at the temperature present in the mixer. The jacket on the mixer may be kept at a temperature from approximately 50 to 100 C., but it is preferred that it be in the range of approximately 66 to 77 C. Steam may be used for heating, and the steam supply controlled to maintain a desired temperature.

The final gelatin composition should have a temperature of from 43 C. to 49 C. for best casting results. The preferred final temperature varies to some extent with the proportions of the components of the composition. If the composition is formed at a higher temperature, it may be cooled during the transferring from the mixer to the holding tank and casting machine. Compositions containing a higher percentage of water should be heated to lower temperatures than compositions containing the lower percentages of water.

By the use of this method of preparing the gelatin composition for casting of the strip, it is found that encapsulation operations are much more flexible because the composition can be prepared in a period of 2 hours. With older procedures, the gelatin composition had to be prepared several days in advance, with the corresponding lack of flexibility in operations.

Further, a single-jacketed mixer can be used with holding tanks for operating several casting machines, thus permitting smaller production runs and more eflicient operations.

Having described certain embodiments thereof, as our invention we claim:

1. A method of preparing a castable gelatin composition which comprises placing subdivided solid dry gelatin in a mixer, evacuating the mixer, agitating the dry gelatin while under vacuum, adding rapidly thereto a mixture comprising water and glycerin at a temperature of between approximately 50 C. and 100 C., intimately and rapidly mixing the water, glycerin and gelatin while maintaining a vacuum, and adjusting the temperature to between about 43 C. and about 85 C.

2. A method of preparing a castable gelatin composition which comprises agitating subdivided dry solid gelatin under a vacuumin a heatedmixer, adding rapidly thereto a mixture comprising water and glycerin at a temperature of between about 50 C. and 100 C. while maintaining the vacuum, rapidly mixing the gelatin and the liquids 6 until homogeneous and adjusting the temperature to between about 43 C. and about C. thereby forming an air bubble free, homogeneous, castable gelatin com position.

3. A method of preparing a castable gelatin composition which comprises agitating subdivided dry solid gelatin under a vacuum in a mixer, adding rapidly thereto water and glycerin at a temperature of between about 50 C. and C., while maintaining the vacuum, and rapidly mixing the gelatin and the liquids until homogeneous, the temperature of the hot liquids, the dry gelatin and the mixer being such that the total heat content is sufficient to give a temperature of between about 43 C. and about 85 C. to the mixed gelatin and liquids in the mixer, immediately on mixing, without supplying additional heat, thereby forming an air bubble free, homogeneous, castable gelatin composition.

4. The method of claim 3 in which the water and glycerin are added simultaneously.

5. The method of claim 3 in which the water is added first, and then the glycerin.

6. The method of claim 3 in which the glycerin is added first, and then the water.

7. The method of preparing a castable gelatin composition which comprises agitating subdivided dry solid gelatin and solid gelatin composition components under a vacuum in a heated mixer, and adding rapidly thereto a mixture comprising water and glycerin at a temperature of between about 50 C. and 100 C. while maintaining the vacuum, rapidly mixing the solids and the liquids until homogeneous, the temperature of the hot liquids, the dry solids, and the mixer being such that the total heat content is sufficient to give a temperature of between about 43 C. and about 85 C. to the mixed solids and liquids in the mixer, immediately upon mixing, without supplying additional heat, thereby forming an air bubble free, homogeneous, castable gelatin composition.

8. The method of claim 1, in Which there is added to the subdivided dry gelatin not more than approximately 80%, by weight based on the finished composition, of residual web.

9. The method of claim 7, in which there is added to the subdivided dry solids initially present in the mixer not more than approximately 80%, by Weight based on the finished composition, of residual web.

10. The method of claim 1, in which, after the addition of the water and glycerin, the agitators are stopped, the vacuum in the mixer is broken, and to the mixed water, glycerin and gelatin in the mixer there is added not more than approximately 80%, by weight based on the finished composition, of residual web, the vacuum is reestablished, the agitators started, and mixing resumed until a homogeneous composition is obtained at a temperature of not less than 43 C.

11. The method of claim 7, in which, after the addition of the water and glycerin, the agitators are stopped, the vacuum in the mixer is broken, and to the mixed water, glycerin and gelatin in the mixer there is added not more than approximately 80%, by weight based on the finished composition of residual web, the vacuum is re-established, the agitators started, and mixing maintained until a homogeneous composition is obtained at a temperature of not less than 43 C.

References Cited in the file of this patent UNITED STATES PATENTS 2,469,546 Calhoun May 10, 1949 2,558,065 Tice June 26, 1951 2,628,916 Scherer Feb. 17, 1953 2,720,463 Stirn et a1. Oct. 11, 1955 

2. A METHOD OF PREPARING A CASTABLE GELATIN COMPOSITION WHICH COMPRISES AGITATING SUBDIVIDED DRY SOLID GELATIN UNDER A VACUUM IN A HEATED MIXER, ADDING RAPIDLY THERETO A MIXTURE COMPRISING WATER AND GLYCERIN AT A TEMPERATURE OF BETWEEN ABOUT 50*C. AND 100*C. WHILE MAINTAINING THE VACUUM, RAPIDLY MIXING THE GELATIN AND THE LIQUIDS UNTIL HOMOGENEOUS AND ADJUSTING THE TEMPERATURE TO BETWEEN ABOUT 43*C. AND ABOUT 85*C. THEREBY FORMING AN AIR BUBBLE FREE, HOMOGENEOUS, CASTABLE GELATIN COMPOSITION. 